The long-term objective of our research is to discover what clinical and molecular changes occur before, during and after severe headaches. Our hypothesis is that the myriad headache triggers and behavioral expressions are mediated through interacting molecular pathways that may be studied by temporal, compositional analysis of accessible body fluids, in particular cerebrospinal fluid (CSF). Preliminary results have revealed many ictal changes in proteins, lipids and elements that reflect these migraine 'gateway' pathways, the magnitude of which reflect the clinical severity of the migraine ictus, suggesting a corresponding 'molecular ictus'. We propose to further dissect this clinical and molecular ictus by the analysis of CSF from migraineurs in headache and non-headache states, episodic tension headache sufferers and 'controls' who do not suffer from headaches. We will test the role of protein, lipid and elemental changes in headache by defining their molecular composition by 2D gel electrophoresis, liquid chromatography and mass spectrometry in temporally spaced collections from clinically well defined participants. Delineation of these compositional differences should extend our pathophysiological understanding beyond the current theories, yield useful biomarkers and lead to more knowledge-based remedies or interventions.